PROJECT SUMMARY/ABSTRACT Risk of HIV acquisition during pregnancy and postpartum is high in sub-Saharan Africa, with incidence rates exceeding 3 per 100 person-years. Incident maternal HIV infections contribute substantially to mother-to-child HIV transmission (MTCT), accounting for 30-46% of all pediatric infections. As coverage of prevention of MTCT (PMTCT) interventions expands, an increasing proportion of HIV infected infants will be attributed to undetected incident maternal HIV, making this an important frontier to address to achieve elimination of MTCT (eMTCT). Strategies to prevent, detect, and treat incident maternal HIV infections will be critical to move towards an HIV-free generation. Recent data suggest transmitted drug resistance (TDR) may be rising among young women of reproductive age. High TDR during pregnancy and/or the postpartum period could compromise effectiveness of maternal antiretroviral therapy (ART), and subsequently increase MTCT risk. Characterizing TDR among peripartum women with recent HIV infections will be important to ensure appropriate ART regimens are utilized in PMTCT programs. In addition, complementary efforts to identify high risk women to target with HIV prevention interventions, such as pre-exposure prophylaxis (PrEP), may bolster testing and treatment approaches for eMTCT. PrEP has been shown to be very effective in non-pregnant women, and safe to use during pregnancy and lactation, but delivering PrEP during and after pregnancy remains a challenge. To optimize PrEP implementation, strategies should maximize prevention efforts by identifying women with the highest risks of maternal HIV acquisition while minimizing unnecessary infant exposure. Simple screening tools for health care workers to identify women most likely to benefit from PrEP would aid programs in service delivery, but have not been externally validated. Data and archived samples collected in an ongoing K01 study in Kenya, which aims to determine the optimal time to conduct repeat maternal HIV testing, will be leveraged to conduct the proposed study. The specific aims are to: 1) externally validate an HIV risk score tool among a cohort of 4650 pregnant/postpartum women, 2) measure maternal HIV viral load and prevalence of TDR among 100 women with incident HIV infection during pregnancy/postpartum, and 3) identify biological and behavioral correlates of maternal HIV infection during pregnancy and postpartum. Together, data from the K01 and R03 studies will provide preliminary data to prepare for a large, implementation science trial to detect and treat incident maternal HIV infections though a repeat maternal HIV testing strategy coupled with targeted screening to determine eligibility for PrEP.